The overall objective of this proposal is to collect data leading to the development of a vaccine able to prevent HIV-1 infection in African American women who are at risk for infection as a direct or indirect consequence of drug abuse. Although they represent only 14% of the female population in the US, African American women make up 66% of all new HIV/AIDS cases among women in reporting states. While direct injection drug use is the second major cause of HIV-1 infections in women, multiple studies have shown that other forms of drug abuse by women, or their partners, are a proximal cause of heterosexual transmission of HIV. Despite their disproportionate risk of infection, few if any vaccine development efforts have focused on African American women. In this proposal, we will first collect data on viruses and antibody responses in this group that could facilitate the development of vaccines designed to elicit broadly neutralizing antibodies (bNAbs). Information of this type includes defining novel epitopes recognized by bNAbs found in these subjects. We will then seek to recover HIV envelope genes from a rare group of subjects who possess high levels of bNAbs and are able to control their viral loads without antiretroviral therapy (ART). While patients able to control viral loads between 50 and 2000 copies/ml and possess bNAbs (viremic controllers) have been known for some time, only recently have individuals able to maintain viral loads at undetectable levels and possess bNAbs been identified. These individuals possess the dual elite neutralizer (EN), elite controller (EC) phenotype. Preliminary data suggest that this phenotype may be more common in HCV-infected African American women than other risk groups. We will then use genetic analysis, including ancestral reconstruction, to recover and characterize the envelope genes that gave rise to bNAb responses in these subjects. We will use these genes to produce recombinant envelope proteins (rgp120 and gp140) and test these as candidate vaccine immunogens in small animal immunogenicity studies. After more than 25 years of vaccine research, none of the HIV vaccines described to date are able to consistently elicit broadly neutralizing antibodies. Moreover, all of the vaccine immunogens in clinical development to date were selected without regard to the neutralizing antibody response in the virus donor. The studies in this proposal will be the first studies to evaluate the efficacy of vaccine immunogens known to have stimulated bNAbs in humans. These will also be the first studies to attempt to replicate the protective immune response seen in a rare group of African American women who have developed effective antiviral immune responses to HIV.